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Neonatal Liquid Dolutegravir Comparable
to Pediatric Dispersible Tablets
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International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020
By Mark Mascolini for NATAP and Virology Education
Two new neonatal liquid formulations of dolutegravir had bioavailability comparable to a dispersible tablet already available for infants at least 4 weeks of age, according to results of a trial in healthy adult men [1]. The study yielded no clinically significant lab values, vital sign measures, or electrocardiogram (ECG) results.
Two pediatric formulations of the HIV integrase inhibitor dolutegravir are available now, film-coated tablets (at doses of 10 and 25 mg) and dispersible tablets (at a 5-mg dose). This trial tested two experimental liquid formulations of dolutegravir: prototype A is a 5-mg/mL dolutegravir suspension in miglyol, and prototype B is a 2-mg/mL dolutegravir solution in glycerol. The goal with these liquid formulations is to achieve dolutegravir exposures similar to those seen in adults.
This trial, study NCT03921723, was an open-label, single-dose, nonrandomized, 3-period, fixed-sequence study [2]. The trial enrolled healthy adult men who took the following dolutegravir doses in three periods separated by at least 7 days without drug: Period 1: prototype A dolutegravir suspension; Period 2: two 5-mg dispersible dolutegravir tablets dispersed in water; Period 3: prototype B dolutegravir solution. All doses were equivalent to 10 mg of dolutegravir. Researchers collected serial samples for 72 hours after each dose and figured geometric least squares (GLS) mean ratios and 90% confidence intervals to compare each liquid formulation to the dispersible tablet.
Twenty-two healthy men between 21 and 49 years old (average 31.3 years) participated in the study. Their weight averaged 79.2 kg and body mass index 25.4 kg/m2. Nineteen men (86%) were white, 2 (9%) black, and 1 (5%) Asian. Twenty-two volunteers took the dispersible tablet, 18 took liquid prototype A, and 19 took liquid prototype B.
After taking prototype A (2 x 5 mg/mL in miglyol), geometric mean area under the concentration-time curve (AUC)(0-infinity), maximum concentration (Cmax), and AUC(0-t) of dolutegravir differed little from dolutegravir exposure after taking two 5-mg dispersible tablets. After taking prototype B (5 x 2 mg/mL in glycerol), AUC(0-infinity) and AUC(0-t) were bioequivalent to exposure with the dispersible tablets, while the upper 90% confidence interval for Cmax was marginally higher (1.33-fold) than with the tablet (GLS mean ratio 1.22, 90% CI 1.13 to 1.33).
The researchers concluded that no dose adjustment of these liquid formulations will be needed when given to neonates.
References
1. Singh R, Shaik J, Wolstenholme A, et al. Comparison of relative bioavailability of TIVICAY neonatal liquid formulations to pediatric dispersible tablets. International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020. Abstract 8.
2. ClinicalTrials.gov. Dolutegravir pediatric liquid formulation study. ClinicalTrials.gov identifier NCT03921723. https://clinicaltrials.gov/ct2/show/NCT03921723
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